Turmeric - curcuminCurcumin is the principal curcuminoid of the popular Indian spice Turmeric, which is a member of the ginger family (Zingiberaceae)

​Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway

Xingxing Zhang†,

Jian Wu†,

Bo Ye,

Qiong Wang,

Xiaodong Xie and

Hong Shen

Abstract​Background Curcumin displays a protective role in rat models of intestinal inflammation. However, the mechanism of how curcumin affects on intestinal inflammation is less known. The purpose of the current study is to explore the signal pathway in which the curcumin protecting rat from intestinal inflammation.

MethodsThe intestinal inflammation rat models were made by TNBS treatment. Curcumin was added to their diet 5 days before the TNBS instillation. After that, body weight change, score of macroscopic assessment of disease activity and microscopic scoring were utilized to analyse the severity of the induced inflammation. In addition, the level of pro-inflammatory cytokines and anti-inflammatory were detected to determine the effect of curcumin on intestinal inflammation. The JAK/STAT pathway of pro-inflammation response was also evaluated. Finally, the impact of curcumin on apoptosis in intestinal inflammation was assessed by TUNEL staining.

ResultsRats pretreated with curcumin significantly reversed the decrease of body weight and increase of colon weight derived from TNBS-induced colitis. Histological improvement was observed in response to curcumin. In addition, curcumin attenuated TNBS-induced secretion of pro-inflammatory cytokines and M1/M2 ratio, while stimulated the secretion of anti-inflammatory cytokines. The inhibition of pro-inflammation response was mediated by SOCS-1, which could efficiently suppress JAK/STAT pathways. Furthermore, curcumin efficiently suppressed the TNBS-induced apoptosis, and reduced the accumulation of cytochrome C in cytosol.

ConclusionThe anti-inflammatory effect of curcumin is realized by enhancing SOCS-1 expression and inhibiting JAK/STAT pathways. Curcumin also plays an anti-apoptotic role in TNBS-induced intestinal inflammation. We propose that curcumin may have therapeutic implications for human intestinal inflammation.

MethodInflammatory bowel disease (IBD) was induced in male Wistar rats by intra-rectal administration of 1 ml of 4 % acetic acid at 8 cm proximal to the anus for 30 s. Curcuma longa (CL) powder, (1, 10, or 100 mg/kg/day) was administered for either 3 days before or after IBD for 7 days. The body weight, macroscopic and microscopic analysis of the colon of CL-treated IBD rats and that of control rats (no IBD, no CL) were performed on 0 day, 2, 4 and 7th day. Myeloperoxidase (MPO), IL-23 and glutathione levels in control, untreated and treated rats were measured by ELISA.

ConclusionCL improved body weight gain, mean macroscopic and microscopic ulcer scores in the colon of rats suffering from acetic acid-induced IBD. CL reduced both MPO and IL-23 in the mucosa of the colon. The increase in the mean serum glutathione level may help in the reduction of oxidative stress associated with IBD.

Plaque psoriasis is an autoimmune, inflammatory skin disorder that causes patches of inflamed, thickened skin lesions. Many patients with psoriasis have other inflammatory disorders, such as metabolic syndrome, Crohn's disease, and cardiovascular disease. Mildly to moderately severe psoriasis is often treated effectively with prescription topical and systemic medications. Topical medications may have undesirable side effects, which include burning, atrophy, and staining of skin and clothes. Turmeric (Curcuma longa, Zingiberaceae) has been used in traditional medicine and found to have anti-inflammatory, antimicrobial, and antioxidant properties. Turmeric extract can decrease the cytokine pro-inflammatory response by inactivating and decreasing the expression of key enzymes in the pro-inflammatory pathway in human cells. Several studies have shown that turmeric extract applied topically can reduce the severity of psoriasis lesions. The goal of this double-blind, placebo-controlled study was to measure the efficacy of turmeric extract microemulgel on the symptoms of psoriasis in patients with mild to moderate plaque psoriasis.

Forty patients between the ages of 18 and 60 years of age with mild to moderate psoriasis on their legs and arms were recruited for the study. Patients were included if the extent and severity of their psoriasis had been stable for at least 2 months. Patients could be taking systemic treatments for psoriasis but were excluded if they were using topical psoriasis treatments. Patients were also excluded if they were taking beta-blockers, had lymphoma, or were pregnant or lactating. Lesions were assessed on each patient. Lesions that were similar in appearance were chosen from the left and right arm and leg. Patients applied a placebo cream to either the left or right side and the turmeric treatment cream to the opposite side. The authors note that the side of the body chosen was randomized, but not whether randomization was done within each patient. The data presented suggest that the turmeric microemulgel was always applied to the right arm and leg and that the placebo was applied to the left side of each patient. The microemulgel was applied twice per day for 9 weeks. The placebo contained only the microemulgel, whereas the treatment contained the microemulgel plus 0.5% of turmeric extracted with water and alcohol (SOHA JISSA Co.; Salman Shahr, Mazandaran, Iran). Curcuminoid concentration of the extract was measured with high-performance liquid chromatography. The redness, thickness, scaling, and area of lesions in each body area were measured with the Psoriasis Area and Severity Index (PASI) every 3 weeks. In addition, patient quality of life was measured at the same time with the Dermatology Life Quality Index (DLQI). Compliance was checked weekly. Data were analyzed with t-tests and chi-squared tests.

Thirty-four patients completed the study. Reasons were not given for the loss of the other patients from the study. The patients noted that stress, changes in temperature, and sun exposure were the most important psoriasis triggers. Within this group of patients, 14.7% had metabolic syndrome, and another 11.8% had diabetes. The number of patients experiencing itching, pain, and social discomfort decreased over the course of the study (P values not given). The redness, thickness, and scaling of lesions on the arms decreased significantly with turmeric treatment over the course of the study (P < 0.05). The scaling of lesions on the legs also decreased significantly with turmeric treatment (P < 0.05). The mean PASI score with turmeric treatment decreased significantly from 3.6 to 1.4 over the course of the study (P < 0.05). The mean PASI score was also significantly lower with the turmeric treatment than with the placebo (P < 0.05). The placebo microemulgel did result in a decrease in the PASI score metrics over the first 3 weeks of the study, but this decrease was not significant. Adverse effects were similar between the turmeric and placebo microemulgels and included dryness and burning.

Turmeric microemulgel significantly reduced the symptoms of psoriasis over a 9-week course of treatment. This treatment also improved quality-of-life indices, although statistical analysis of these indices was not provided. In addition, the turmeric microemulgel was well tolerated with few adverse effects. Other studies have found that phosphorylase kinase (PK) expression is higher in patients with psoriasis and that curcuminoids inhibit PK activity. PK is integral to the pro-inflammatory response, and its inhibition should result in a decrease in inflammation. This study may have been limited by the small sample size and type of randomization used. The type of randomization is not adequately described, but the results suggest that the use of the turmeric microemulgel was randomized to the right side of the body for all patients. This may cause unwanted bias. The results of this study suggest that turmeric may be an effective topical treatment for psoriasis with few side effects.--Cheryl McCutchan, PhD ​

AbstractAcne is a cutaneous pleomorphic disorder of the pilosebaceous unit involving abnormalities in sebum production and is characterized by both inflammatory (papules, pustules and nodules) and non-inflammatory (comedons, open and closed) lesions. Propionibacterium acnes and Staphylococcus epidermidis are common pus-forming microbes responsible for the development of various forms of Acne vulgaris. The present study was conducted to evaluate antimicrobial activities of seven medicinal plants against acne-inducing bacteria. Acetonic and aqueous extracts of Azadirachta indica (leaves), Curcuma longa (root), Aloe vera (leaves), Withaniasomnifera (leaves), Terminalia arjuna (bark), Ocimim sanctum(leaves), Santalum album (wood) were tested for antimicrobial activities by agar diffusion, Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) methods. The results from the agar diffusion method showed that five medicinal plants could inhibit the growth of acne-inducing bacteria. Among these Azadirachta indica,Curcuma longa and Terminalia arjuna had strong inhibitory effects. Based on MIC, the acetonic extracts of Azadirachta indica and Curcuma longa had the greatest antimicrobial effects. Taken together, the present study indicated that Azadirachta indica had a strong inhibitory effect on acne-inducing bacteria.

AbstractMetabolic syndrome (MetS) is characterized by abdominal obesity and the co-occurrence of at least 3 of the following: high blood pressure (BP), elevated fasting blood glucose (FBG), high serum triglyceride (TG) levels, and low concentrations of high-density lipoprotein cholesterol (HDL-C). Medicinal plants may be used along with exercise and dietary modification to treat and prevent MetS as they contain bioactive phytochemicals with diverse metabolic effects. Experimental and clinical studies have shown that turmeric (Curcuma longa, Zingiberaceae) rhizome and nigella (Nigella sativa, Ranunculaceae) seed have hypolipidemic, hypoglycemic, and antioxidant effects. These authors followed up their 2014 study1 showing the synergistic effects of these herbs by conducting a randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of these herbs alone and in combination among patients with MetS.Patients were recruited from "a small community, Hijrat Colony, an urban-slum located at Mai-Kolachi, Karachi, Pakistan." Male residents of the colony with a waist circumference (WC) ˃90 cm (35.4 inches), along with 3 or more features of MetS, and who were not on regular medications were recruited. The exclusion criteria were as follows: hypertension or coronary heart disease; taking herbal supplements; on medications for hyperlipidemia, obesity, or chronic disease; and debilitation. The sample size was calculated for a 5% level of significance and a power of 80%. Assuming a 20% non-participation rate, at least 62 patients in each group were required.A total of 250 patients (mean age, 44 ± 13.3 years) were randomly assigned to receive 1 of the following treatments daily for 8 weeks:

The selected dosage of the interventions was based on data from other studies. The source of the plant powders and their phytochemical characteristics were not reported. The patients visited the research site weekly to receive more capsules; compliance and adverse effects were also queried at each visit. In addition, compliance and adverse effects were monitored weekly by drug diary, phone calls, and bi-weekly visits by research officers in case of no contact. The patients were given education on lifestyle modifications to prevent and manage MetS at baseline and at 4 and 8 weeks.At baseline and at the end of the study, the patients completed diet and physical activity questionnaires. Blood samples were drawn at baseline and after 4 and 8 weeks; they were analyzed to determine plasma levels of FBG, C-reactive protein (CRP), cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, and TGs. BP, WC, hip circumference (HC), and body mass index (BMI) were assessed at baseline and every 2 weeks.At baseline, there were no significant differences among the groups in clinical characteristics. There were 6-9 withdrawals in each group. One patient in the nigella group quit due to nausea and 1 patient in the combination group dropped out due to excessive weakness, while in the turmeric group, 3 patients withdrew due to nausea and 1 due to skin pruritus (itching).Compared to baseline, BMI, body fat percentage, and BP improved in all groups, but there were no significant differences among the groups. The authors attributed these improvements to lifestyle modifications.After 8 weeks, TGs (P=0.001), cholesterol (P=0.02), FBG (P=0.02), LDL-C (P<0.001), and HDL-C (P=0.02) were significantly improved in the nigella group compared with placebo; however, when compared with baseline values, only cholesterol (P<0.001) and TGs (P<0.001) were significantly improved.Compared with placebo, turmeric alone was more effective in reducing total cholesterol (P=0.009), LDL-C (P<0.001), and CRP (P<0.001), but had no significant effect on blood glucose. However, the effect on lipids was not significant compared to baseline.In the combination group, improvements were observed in all clinical parameters compared with baseline values. Compared with the placebo group, greater improvements were seen in CRP (P=0.007), body fat percentage (P=0.04), total cholesterol (P=0.02), FBG (P<0.001), TGs (P=0.03), LDL-C (P<0.001), and HDL-C (P=0.04). Compared with the nigella group, the combination group showed greater improvements in HC (P=0.001), body fat percentage (P=0.008), weight (P<0.001), TGs (P=0.02), and CRP (P<0.001).Although the occurrence of mild adverse effects was the highest in the turmeric group, there was no significant difference among groups. One patient in the nigella group and 3 patients in the turmeric group reported nausea, but there were no reports of nausea in the combination group. The authors suggest that this may be due to the lower dose of turmeric in the combination or the presence of nigella in the combination.In summary, nigella alone improved lipid profiles and FBG and turmeric alone reduced LDL-C and CRP levels compared to placebo. However, the combination of nigella and turmeric (at 60% lower doses) improved several MetS parameters; the combination reduced body fat percentage, FBG, CRP, and improved lipid profiles. The study is limited by the failure to characterize the botanicals. These results need to be confirmed in longer-duration studies of larger and more ethnically diverse populations using herbs that have been chemically profiled.―Shari Henson

AbstractCurcumin is the main curcuminoid found in the yellow spice turmeric, a prominent member of the ginger family. Studies have revealed that curcumin exhibits numerous beneficial effects such as the ability to reduce inflammation and oxidative stress. The present study examines the neuroprotective effects of curcumin in vitro by subjecting B35 and SH-SY5Y neuroblastoma cells to hydrogen peroxide (H2 O2 ) followed or preceded by treating them with curcumin. Using curcumin concentrations of 5, 10 and 20 µM before and after damaging the cells with H2 O2 has resulted in an increase in cell viability of B35 neuroblastoma cells. In contrast, SH-SY5Y neuroblastoma cells showed an increase in their viability only upon the post-treatment with curcumin. The inhibitory effect of curcumin on caspase-3 and caspase-9, two of the most important mediators in the process of apoptosis, was also examined. We found that curcumin inhibited caspase-3 in a concentration-dependent manner, but not caspase-9. Using 5, 10, and 20 µM of curcumin resulted in 2.6%, 7.9% and 12.2% caspase-3 inhibition, respectively. These findings suggest that curcumin acts as a neuroprotectant and an anti-apoptotic agent through the inhibition of caspase-3, thereby introducing a potential agent for the treatment or prevention of neurodegenerative diseases.

ConclusionsOral curcumin likely reduces pain associated with DOMS with some evidence for enhanced recovery of muscle performance. Further study is required on mechanisms and translational effects on sport or vocational performance.

AbstractThis study measures the curcumin concentration in rat plasma by liquid chromatography and investigates the changes in the glucose tolerance and insulin sensitivity of streptozotocin-diabetic rats treated with curcumin-enriched yoghurt. The analytical method for curcumin detection was linear from 10 to 500 ng/mL. The Cmax and the time to reach Cmax (Tmax) of curcumin in plasma were 3.14 ± 0.9 μg/mL and 5 minutes (10 mg/kg, i.v.) and 0.06 ± 0.01 μg/mL and 14 minutes (500 mg/kg, p.o.). The elimination half-time was 8.64 ± 2.31 ​​(i.v.) and 32.70 ± 12.92 (p.o.) minutes. The oral bioavailability was about 0.47%. Changes in the glucose tolerance and insulin sensitivity were investigated in four groups: normal and diabetic rats treated with yoghurt (NYOG and DYOG, resp.) and treated with 90 mg/kg/day curcumin incorporated in yoghurt (NC90 and DC90, resp.). After 15 days of treatment, the glucose tolerance and the insulin sensitivity were significantly improved in DC90 rats in comparison with DYOG, which can be associated with an increase in the AKT phosphorylation levels and GLUT4 translocation in skeletal muscles. These findings can explain, at least in part, the benefits of curcumin-enriched yoghurt to diabetes and substantiate evidences for the curcumin metabolite(s) as being responsible for the antidiabetic activity.

AbstractAlzheimerʼs disease is a chronic neurodegenerative disorder characterized by progressive dementia and deterioration of cognitive function. Although several drugs currently used for the treatment of Alzheimerʼs disease delay its onset and slow its progression, still there is no drug with profound disease-modifying effects. Studies aiming the treatment of this neurodegenerative disorder explore various disease mechanisms. Since antiquity, medicinal herbs have been used in traditional medicine. Recent studies suggest that the neurobiological effects of phytochemicals from medicinal herbs may contribute to clinical benefits in in vitro and in vivo models of Alzheimerʼs disease. This review focuses on five phytochemicals, berberine, curcumin, ginsenoside Rg1, puerarin, and silibinin, which have been mostly investigated to treat the development and progression of this neurodegenerative disorder.....To date, evidence from recent studies suggests that commonly used medicinal herbs and their phytochemicals could potentially be used to treat AD. Although these studies focus on the efficacy of inhibiting AD development, and research on humans is limited, numerous findings demonstrate the possibilities of the use of medicinal herbs for the treatment of AD. The approach to investigate the potential treatment of AD may support drug development from herbal medicine.

The most common joint disease in adults, osteoarthritis (OA) is characterized by chronic joint pain, inflammation, stiffness, and limited mobility. Standard treatment is the prescription of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs); however, NSAIDs are only partially effective and may cause adverse gastrointestinal, renal, and cardiovascular effects. Experimental studies have found that the curcuminoid constituents (2-5%) of turmeric (Curcuma longa, Zingiberaceae) have significant analgesic, anti-inflammatory, and antioxidant properties. Preliminary clinical evidence suggests curcuminoids may be an effective alternative or adjunct treatment for OA. In this randomized, double-blind, placebo-controlled pilot study, the effect of curcuminoid supplementation on clinical measures of knee OA symptoms was measured.

Patients under the age of 80 with mild-to-moderate knee OA (n=60) were recruited from Baqiyatallah University Clinic in Tehran, Iran. Diagnoses of knee OA were based on the clinical and radiological criteria of the American College of Rheumatology and a minimum score of 40 mm on a 100 mm visual analog scale (VAS) of joint pain. The exclusion criteria were as follows: known allergy to curcuminoids or other herbs; candidates for knee replacement or any other surgery; OA secondary to trauma; rheumatoid arthritis, inflammatory disorders, or hemophilia; malabsorption disorders; active, generalized inflammatory conditions; heart, renal, or liver failure; history of psychological disorders; using ˃10 mg/day corticosteroids in the prior 3 months; and intra-articular injections in the last 3 months.

The eligible consenting patients (n=53) were consecutively randomly assigned to receive either 500 mg 3x/day (1500 mg/day) of curcuminoids (n=27; C3 Complex®; Sami Labs Ltd; Bangalore, India) or a size- and shape-matched placebo (n=26; inert starch) for 6 weeks. Each C3 Complex capsule contained 500 mg curcuminoids and 5 mg BioPerine® (Sami Labs Ltd). BioPerine is a standardized extract of black pepper (Piper nigrum, Piperaceae) and/or long pepper (Piper longum) containing at least 95% piperine, which has been shown to increase the absorption of curcuminoids. All patients were allowed to use an escape medication (naproxen) when they had intolerable pain.

The change in OA symptoms was measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), OA pain severity rating on VAS, and the 5-item Lequesne's Pain Functional Index (LPFI). Adverse effects were recorded using a pre-designed checklist.

Forty patients completed the study with 19 in the treatment group and 21 in the placebo group. Eight patients in the treatment group and 5 patients in the placebo group were lost to follow-up. No reasons for the losses in either group were given. All patients were taking NSAIDs at baseline.

At the end of the study, there were significant reductions in the global WOMAC score and the pain, physical function, and stiffness subcategory scores in the treatment group (P < 0.001, P < 0.001, P < 0.001, and P = 0.043, respectively) compared to baseline. The scores for the WOMAC pain and stiffness subcategories were also significantly reduced in the placebo group (P = 0.025 and P = 0.009, respectively) compared to baseline. However, the global WOMAC score and scores for the subcategories of pain and physical function were all significantly lower in the treatment group compared to the placebo group at the end of the study (P = 0.001, P < 0.002, and P < 0.001, respectively). There was no significant difference between the treatment and placebo groups in the WOMAC stiffness subcategory.

Treatment with curcuminoids (but not placebo) significantly improved both the VAS and LPFI scores (P < 0.001 for both) compared to baseline. Compared to the placebo group, the magnitude of reduction in VAS and LPFI scores was significantly greater in the treatment group (P = 0.013 and P < 0.001, respectively). There was also a significant reduction (P < 0.001) in the use of NSAIDs in the treatment group (84%) compared to the placebo group (19%). No serious adverse events (AEs) were reported, and none of the dropouts were due to AEs. The most common AE was gastrointestinal distress with 7 patients in the treatment group and 4 in the placebo group affected.

Six weeks of curcuminoid supplementation resulted in marked improvement in symptoms of knee OA compared to the placebo. In addition, there was a significant reduction in the use of NSAIDs in the group taking curcuminoid supplements. The authors suggest that a plausible mechanism is the potent anti-inflammatory and antioxidant properties of curcuminoids. Curcuminoids have been shown to reduce the release of pro-inflammatory cytokines in cultured chondrocytes, increase chondrocyte survival, inhibit the production of reactive oxygen species which impair joint components, and scavenge free radicals which disrupt the cartilage matrix and promote the production of pain mediators.

The authors note several limitations of the study, including the small sample size and short duration, as well as the facts that the optimum dose and dose-response relationship were not determined and only patients with mild-to-moderate OA were evaluated. Based upon the positive safety and efficacy findings in this study, the authors conclude that larger scale (Phase III) trials should be conducted to confirm the results and investigate whether the effect is independent of analgesic mechanisms.

AbstractBackground and Objectives. Curcumin has long been used to treat age-related diseases, such as atherosclerosis and coronary heart disease. In this study, we explored the effects of curcumin on the development of abdominal aortic aneurysm (AAA).

Results. The results showed that curcumin treatment significantly decreased the occurrence of AAA. The levels of macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factors-α (TNF-α) were significantly lower in AngII + Cur group than those in AngII group (all ). The level of superoxide dismutase (SOD) was significantly higher in AngII + Cur group than those in AngII group . The ERK1/2 phosphorylation in AngII + Cur group was significantly lower than that in AngII group .

Conclusions. These results suggested that curcumin can inhibit the AngII-induced AAA in ApoE−/− mice, whose mechanisms include the curcumin anti-inflammation, antioxidative stress, and downregulation of ERK signaling pathway.

(Curcuma aromatica (common name: wild turmeric) is a member of the Curcuma genus belonging to the family Zingiberaceae. Botanically close to Curcuma australasica, wild turmeric has been widely used as a cosmetic herbal in South Asia...)

AbstractBackground Curcuma aromatica oil is a traditional herbal medicine demonstrating protective and anti-fibrosis activities in renal fibrosis patients. However, study of its mechanism of action is challenged by its multiple components and multiple targets that its active agent acts on.

Methodology/Principal FindingsNuclear magnetic resonance (NMR)-based metabonomics combined with clinical chemistry and histopathology examination were performed to evaluate intervening effects of Curcuma aromatica oil on renal interstitial fibrosis rats induced by unilateral ureteral obstruction. The metabolite levels were compared based on integral values of serum 1H NMR spectra from rats on 3, 7, 14, and 28 days after the medicine administration. Time trajectory analysis demonstrated that metabolic profiles of the agent-treated rats were restored to control levels after 7 days of dosage. The results confirmed that the agent would be an effective anti-fibrosis medicine in a time-dependent manner, especially in early renal fibrosis stage. Targeted metabolite analysis showed that the medicine could lower levels of lipid, acetoacetate, glucose, phosphorylcholine/choline, trimethylamine oxide and raise levels of pyruvate, glycine in the serum of the rats. Serum clinical chemistry and kidney histopathology examination dovetailed well with the metabonomics data.

Conclusions/SignificancesThe results substantiated that Curcuma aromatica oil administration can ameliorate renal fibrosis symptoms by inhibiting some metabolic pathways, including lipids metabolism, glycolysis and methylamine metabolism, which are dominating targets of the agent working in vivo. This study further strengthens the novel analytical approach for evaluating the effect of traditional herbal medicine and elucidating its molecular mechanism.

Comparative antiulcer effect of bisdemethoxycurcumin and curcumin in a gastric ulcer model system

Abstract

The antiulcer effect of bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application as a remedy for peptic ulcer. Western blot analysis of mouse macrophage cell line RAW 264.7 activated with lipopolysaccharide showed that bisdemethoxycurcumin inhibited inducible nitric oxide synthase (iNOS) production significantly but had no effect on tumor necrosis factor-alpha (TNF-[alpha]) production, whereas curcumin showed stronger suppression of iNOS protein production and inhibited TNF-[alpha] protein production significantly. However, bisdemethoxycurcumin and curcumin possessed similar potency in scavenging nitric oxide generated from mouse macrophage cell line RAW 264.7. Reversetranscriptase polymerase chain reaction (RT-PCR) analysis showed that both curcuminoids inhibited the induction of iNOS dose-dependently at the transcriptional level and curcumin also appeared to inhibit the induction of TNF-[alpha] at post-transcriptional level. In an animal model, intraduodenal administration of bisdemethoxycurcumin (5-80 mg/kg body wt.) showed a strong inhibitory effect on gastric acid secretion in pylorus-ligated rats whereas curcumin (5-20 mg/kg body wt.) showed a less inhibitory effect, with maximum potency at a dose of 20 mg/kg body wt. Moreover, oral administration of bisdemethoxycurcumin at doses of 20-80 mg/kg body wt. twice daily for 10 days showed a significant curative efficacy in accelerating the healing of acetic acid-induced chronic gastric ulcer and promotion of mucosal regeneration in the ulcerated portion in a dose-related manner with potency equal to curcumin. In contrast, the curative potency of curcumin tended to decrease at doses over 160 mg/kg body wt./day. Western blot analysis in ulcerated gastric mucosa showed that bisdemethoxycurcumin dose-dependently reduced the increased protein expression level of iNOS but not TNF-[alpha]. These results indicated that bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin. Its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.

AbstractCurcuma longa (Turmeric) is a bright yellow ancient spice native to Asian countries. It has been used as traditional remedy dating back to 600 BC. Turmeric is well known for its applications as a cosmetic, condiment and flavoring agent. The present study was an attempt to explore the protective effect of Curcuma longa rhizomes against physical stress-induced perturbations in rats. Animals were pre-treated with extracts of C. longa rhizomes (crystallized ethylacetate extract; and byproduct-oleoresin) at doses of 200 and 400 mg/kg for 21 days. The effect on swimming endurance followed by post-swimming muscle co-ordination and spontaneous motor activity was evaluated. Estimation of brain monoamine levels in rats and HPLC analysis were carried out. Pre-treated rats with C. longa extracts showed dose dependant significant enhancement in swimming endurance time, increased the duration (sec) of stay on rota-rod apparatus and increased the count (actophotometer score) in spontaneous motor activity. In addition, the pre-treated rats were found to possess normalizing activity against physical stress induced changes in norepinephrine, dopamine and serotonin. Curcuminoids was identified by HPLC analysis and it was one of the active principles responsible for the adaptogenic activity. Extracts of C. longa rhizomes exhibited adaptogenic activity against physical stress model followed by post-swimming muscle co-ordination and spontaneous motor activity, which could be due to the presence of curcuminoids content. In conclusion, the results of the present investigation emphasized the protective effect of C. longa rhizomes against physical stress-induced perturbations in rats.

Eccentric exercise refers to forced muscle elongation during muscle contraction. This form of exercise may lead to mild muscle damage and delayed onset muscle soreness (DOMS), the generation of reactive oxygen species (ROS), and subsequent inflammation. Curcumin, a compound isolated from turmeric (Curcuma longa) root, has been shown to have anti-inflammatory activity1 by attenuating the modulators of inflammation, including nuclear factor kappa B (NF-ĸB) and cyclooxygenase-2 (COX-2)2,3; curcumin has also been reported to activate endogenous antioxidant response modulator nuclear factor erythroid 2-related factor 2 (Nrf2).4 This randomized, placebo-controlled, single-blind trial investigated the potential of curcumin product Meriva® (Indena S.p.A.; Milan, Italy), formulated with soy (Glycine max) lecithin to enhance bioavailability, to alleviate muscle injury, ROS damage, and inflammation due to eccentric exercise.

This study enrolled 20 healthy men that engaged in aerobic exercise for 4 hours per week or more. Included subjects did not smoke, had no diseases of the musculoskeletal system, and had a maximal oxygen consumption (VO2max) of 35 ml/kg or greater during a treadmill exercise test. Those taking anti-inflammatory, analgesic, or antioxidant medications in the past month; with liver or kidney problems; or with current inflammation or disease were excluded. Subjects were randomly assigned to either 1 g of Meriva 2 times per day at breakfast and dinner, for a total curcumin dosage of 400 mg daily, or placebo. Meriva contains curcumin (20%), soy lecithin in a 1:2 weight ratio, and 2 parts of microcrystalline cellulose. Contents of the placebo were not described. Treatments were given 48 hours before downhill-run testing and continued for 24 hours following the testing for a total of 4 days.

Subjects underwent a baseline treadmill exercise test at a 3% grade starting at 6 km/h, raised by 1 km/h per minute until either VO2max was steady or began to decrease, or muscle fatigue occurred. VO2max, maximum speed (Spdmax), and speed at anaerobic threshold (Spdat) was determined. After 2 days of curcumin, to induce eccentric muscle injury, a downhill running test was conducted, consisting of a 10-minute warm-up and a downhill run at constant speed on a treadmill at -10% for 45 minutes. At 7 and 5 days before the curcumin intake began, subjects had conducted 10-minute exercise regimes to practice the study protocol and ensure a consistent baseline of muscle tone. Additionally, subjects were given a "nutritional supplement" of 25-30 g of carbohydrates and 2-4 g of protein 1 hour before the downhill running test. Subjects were given access to water ad lib during the downhill running test after consuming 500 ml of mineral water 30 minutes before the test began.

Magnetic resonance imaging (MRI) was used to gauge thigh muscle damage, and muscle biopsies were taken 48 hours after the downhill running test to assess for muscle myeloperoxidase (MPO) activity, albumin, and cluster of differentiation 3 (CD3) positive cells using immunohistochemistry (all markers of muscle injury or inflammation). A week before the test, blood cell and blood chemistry parameters had been assessed. Blood was also taken right before the downhill running test, and 2 and 24 hours after the test, to measure markers of both oxidative stress and inflammation. Pain was also measured 48 hours after the test by a scale ranging from 0 (no pain) to 4 (disabling pain) while climbing up or down stairs.

Of the 20 subjects enrolled, 1 subject randomly assigned to the Meriva group dropped out for personal reasons prior to the test, leaving 9 subjects in the Meriva group. Between the placebo and Meriva groups, no significant differences were noted in Spdmax (13.7 ± 1.8 km/h vs. 14.8 ± 1.1 km/h) or downhill running speed (10.9 ± 1.2 km/h vs. 11.4 ± 0.9 km/h). According to the MRI measurements, a significantly less percentage of subjects had muscle damage in the Meriva group as compared to the placebo group in the posterior (44.4% vs. 90%, P=0.0329) or medial (33.3% vs. 80%, P=0.0397) areas of the right thigh. Results were similar in the left thigh (33.3% vs. 80%, P=0.0397, and 33.3% vs. 90%, P=0.0106, respectively).

Overall, the difference in pain experienced by the Meriva group as compared to the placebo group approached significance (23.3 ± 7.9 vs. 30.6 ± 7.9, P=0.06). When analyzing the anterior thigh area, both right and left comparisons showed significantly less pain in the Meriva group (right=4.4 ± 2.5 vs. 7.8 ± 3.9, left=4.4 ± 2.4 vs. 8.2 ± 4.6, P<0.05 for both). Also, at the 2-hour post-exercise test, interleukin-8 (IL-8, a marker of inflammation) was significantly lower in the Meriva group as compared to the control (196.8 ± 66.1 pg/ml vs. 274.7 ± 70.7 pg/ml, P<0.05). Markers of oxidant stress were not significantly different between groups at any time. Muscle biopsy endpoints (n=4 from the Meriva group, and n=5 from the placebo group) were not significantly different between groups.

This study showed a significant reduction in muscle damage, pain in certain areas, and IL-8 concentrations associated with Meriva consumption during eccentric exercise, pointing to its potential use in preventing DOMS. No effect was noted on markers of oxidative stress; this suggests that curcumin likely attenuates inflammation as opposed to oxidant damage. The authors mention that curcumin may activate endogenous antioxidant regulatory cellular mechanisms and may also act as an analgesic. Limitations of this study include the short duration, single type of aerobic exercise employed, the overall small amount of oxidative damage, and the limited amount of biopsy samples. Ideally, future studies will focus on specific mechanism of action during use with exercise.

Human papillomavirus (HPV), a common infection, is considered to be the underlying cause of most cervical cancers, especially HPV 16 and HPV 18. Curcumin, a compound found in turmeric (Curcuma longa) root, has been reported in preclinical studies to kill cervical cancer cells. Additionally, amla (Phyllanthus emblica syn. Emblica officinalis) and aloe (Aloe vera) in very low concentrations have been found to inhibit transduction of a form of HPV.1 This randomized, double-blind, placebo-controlled trial investigated a cream product known as Basant™, designed by the Talwar Research Foundation; New Delhi, India. Basant contains curcumin, amla extract, Chinese soapberry (reetha; Sapindus mukorossi), aloe, and French rose (Rosa gallica) water. Basant was compared with a placebo cream and curcumin and placebo vaginal capsules to investigate the clearing of HPV cervical infections in women who are positive for HPV but free from cancer.

Included women were between 30-60 years old, had diagnosed cervical HPV, with no evidence of cancer or high-grade squamous intraepithelial lesions (HSIL, a form of pre-cancerous pathology), and agreed to use "barrier" contraception during the study. Those with low-grade squamous intraepithelial lesions (LSIL, mild pathology) were included. Those pregnant or lactating or who had more than a 7-day menstrual period, had undergone previous treatment for cervical cancer, or had any serious illness that could interfere with the study were also excluded. In total, 280 patients were intended for randomization into Basant, placebo cream, curcumin capsules, or placebo capsules groups (n=70 per group). However, only 54 patients were enrolled in the placebo cream group as the placebo cream was in short supply from the manufacturer. Neither the content nor the manufacturers of the placebo or curcumin capsules are described.

Patients were screened and randomly assigned in 14 days, with leftover material used to gauge compliance. Treatments were applied once per day for 30 days except during menstruation. Exact times and amount of clinical visits and follow-up are not well described. At baseline and at the end of the study, Pap smears and cervical samples for HPV detection were collected, colposcopy (microscopic exam) was conducted, and biopsy was done if problems were seen at screening or colposcopy. Polymerase chain reaction (PCR) was used to characterize HPV. Functional assessments of liver and kidneys and hematology were also completed. Adverse events (AEs) were measured and scaled according to mild, moderate, or severe, along with correlation to treatments. All patients enrolled were analyzed for AEs.

In total, 287 women were enrolled in the study, with a significantly greater amount of postmenopausal patients in the placebo cream group as compared to the Basant group (P=0.02). From the total amount of patients, 255 finished the protocol (per-protocol analysis). Those that dropped out due to ASEs but completed the third clinic visit (7 in the Basant group, 3 in the placebo cream group, 2 in the curcumin group, and 1 in the placebo capsule group) were included in the Modified Intention To Treat (MITT) analysis, along with 1 patient that did not complete the full dosage (66 patients in the Basant group, 48 patients in the placebo cream group, 75 patients in the curcumin group, and 80 in the placebo capsule group).

According to the MITT analysis, HPV was cleared in 87.7% of those using Basant cream, in comparison to clearance in 75.0% of those in the placebo cream group; the difference between the 2 groups was notable, but not statistically significant (P=0.08). In the curcumin capsule group, the number of patients (81.3%) who had clearance of HPV was not significantly higher compared to 72.5% of those in the placebo capsule group (P=0.19). When the Basant group results were compared to the combined placebo groups, the difference was significant (P=0.03), but this approach defies the principle of randomized controlled trials.

There were no significant differences in rates of clearance between the Basant cream and curcumin capsule treatment and their respective placebos in the MITT population. Those using Basant cream all (17/17) showed eradication of both HPV 16 and HPV 18 infections, while 85.7% (12/14) of those in the curcumin group cleared the infection; 78.6% (22/28) of those in both placebo groups combined showed eliminated infection. In the Basant group, 57.1% of those with LSIL (4/7 patients) had decreased lesions, while the 2 patients with LSIL in the placebo cream group had no lesions at the end of the study. Two of the 6 patients with LSIL in the curcumin capsule group showed clearance of these lesions, while no one in the placebo capsule group had these lesions at the start of the study.

In the Basant group, 20 patients had AEs, in comparison to 4 patients in the placebo cream group. This difference was significant (P=0.005). Vulvo-vaginal burning was the most common AE in the Basant group (n=12), followed by vulvo-vaginal pruritus (itching; n=10). However, there were no significant differences in the number of AEs reported in the curcumin group compared to the placebo capsule group (12 versus 9 AEs).

Although there was a greater rate of HPV elimination in the Basant group for HPV 16 and HPV 18 as compared to the placebo group (which was not significant [P=0.07]), this product may be clinically useful in treating HPV and preventing cancer. It is suggested that synergy among the botanicals used may enhance bioactivity. Despite this, Basant treatment resulted in significantly more AEs than the placebo group, suggesting that this product may not be well tolerated. Other limitations discussed include the small sample size in the placebo cream group, combined analysis of the 2 placebo groups, and small number (and inclusion) of patients with LSIL. Additionally, the lack of a comparison of standard pharmaceuticals used to treat HPV to Basant or curcumin treatment is not explained. Also, no rationale is provided for the curcumin formulation employed. Ideally, larger future trials with longer follow up will further address efficacy and tolerability of Basant for HPV clearance. --Amy C. Keller, PhDReference1Talwar GP, Dar SA, Rai MK, et al. A novel polyherbal microbicide with inhibitory effect on bacterial, fungal and viral genital pathogens. Int J Antimicrob Agents. 2008;32(2):180-185.

AbstractBackground The management of osteoarthritis (OA) remains a challenge. There is a need not only for safe and efficient treatments but also for accurate and reliable biomarkers that would help diagnosis and monitoring both disease activity and treatment efficacy. Curcumin is basically a spice that is known for its anti-inflammatory properties. In vitro studies suggest that curcumin could be beneficial for cartilage in OA. The aim of this exploratory, non-controlled clinical trial was to evaluate the effects of bio-optimized curcumin in knee OA patients on the serum levels of specific biomarkers of OA and on the evaluation of pain.

Methods Twenty two patients with knee OA were asked to take 2x3 caps/day of bio-optimized curcumin (Flexofytol®) for 3 months. They were monitored after 7, 14, 28 and 84 days of treatment. Pain over the last 24 hours and global assessment of disease activity by the patient were evaluated using a visual analog scale (100 mm). The serum levels of Coll-2-1, Coll-2-1NO2, Fib3-1, Fib3-2, CRP, CTX-II and MPO were determined before and after 14 and 84 days of treatment.

Results The treatment with curcumin was globally well tolerated. It significantly reduced the serum level of Coll2-1 (p < 0.002) and tended to decrease CRP. No other significant difference was observed with the other biomarkers. In addition, curcumin significantly reduced the global assessment of disease activity by the patient.

Conclusion This study highlighted the potential effect of curcumin in knee OA patient. This effect was reflected by the variation of a cartilage specific biomarker, Coll2-1 that was rapidly affected by the treatment. These results are encouraging for the qualification of Coll2-1 as a biomarker for the evaluation of curcumin in OA treatment.

AbstractAluminium is a potent neurotoxin and has been associated with Alzheimer's disease (AD) causality for decades. Prolonged aluminium exposure induces oxidative stress and increases amyloid beta levels in vivo. Current treatment modalities for AD provide only symptomatic relief thus necessitating the development of new drugs with fewer side effects. The aim of the study was to demonstrate the protective effect of chronic curcumin administration against aluminium-induced cognitive dysfunction and oxidative damage in rats. Aluminium chloride (100 mg/kg, p.o.) was administered to rats daily for 6 weeks. Rats were concomitantly treated with curcumin (per se; 30 and 60 mg/kg, p.o.) daily for a period of 6 weeks. On the 21st and 42nd day of the study behavioral studies to evaluate memory (Morris water maze and elevated plus maze task paradigms) and locomotion (photoactometer) were done. The rats were sacrificed on 43rd day following the last behavioral test and various biochemical tests were performed to assess the extent of oxidative damage. Chronic aluminium chloride administration resulted in poor retention of memory in Morris water maze, elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant increase in the acetylcholinesterase activity and aluminium concentration in aluminium treated rats. Chronic administration of curcumin significantly improved memory retention in both tasks, attenuated oxidative damage, acetylcholinesterase activity and aluminium concentration in aluminium treated rats (P<0.05). Curcumin has neuroprotective effects against aluminium-induced cognitive dysfunction and oxidative damage.

Chronic kidney disease (CKD), which affects about 20 million Americans, is expected to rise in incidence because of the increase in diabetes, hypertension, and obesity. CKD is characterized by a chronic inflammatory state, with elevated levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in all stages of the disease. Patients with CKD also exhibit lower levels of plasma glutathione peroxidase (GPx) and other antioxidant enzymes. In most patients, CKD is not diagnosed early when the disease is asymptomatic, which is of concern because of the relationship between the systemic inflammation of the disease and the risk for cardiovascular disease (CVD). In addition to pharmaceuticals such as statins and angiotensin-converting enzyme inhibitors, complementary and alternative medicine therapies used to treat CKD are gaining interest in the scientific community. The authors conducted a study to evaluate the inflammatory and antioxidant responses of 8 weeks of curcumin (from turmeric; Curcuma longa) and boswellia (Indian frankincense; Boswellia serrata) supplementation in patients with mild-to-moderate CKD.

Patients at a community health center in Central Texas who were older than 18 years of age and had CKD in stages 1 through 5 were recruited for the study. Patients completed a medical history questionnaire and underwent a general physical examination by their physician to determine eligibility. The patients were randomly chosen to receive an herbal supplement of curcumin and boswellia (824 mg purified turmeric extract, 95% curcuminoids, and 516 mg boswellia extract, 10% 3-acetyl-11-keto-β-boswellic acid) or placebo (roasted rice [Oryza sativa] powder). The study supplement was added to the patients' existing treatment protocols. The study outcome variables were plasma IL-6, TNF-α, GPx, and serum C-reactive protein (CRP).

The patients participated in 2 testing sessions 8 weeks apart. During session 1, they donated blood after a 12-hour fast and underwent measurements for height, weight, heart rate, blood pressure, and waist and hip circumferences. They were then given an 8-week supply of the supplement or placebo and instructed to ingest 2 capsules daily (1 in the morning with breakfast and 1 in the evening with dinner) and to continue their usual medications. After 8 weeks, the patients returned to the clinic for another blood draw and a pill count to determine compliance. The patients' diets were not standardized; they maintained their normal dietary habits during the study.

Sixteen patients (out of an original 23) completed the study. At baseline, the placebo group (n=7) had significantly higher values for height (P=0.05), body mass index (BMI) (P=0.01), waist circumference (P=0.03), and hip circumference (P=0.02). Glomerular filtration rate (GFR), used to determine kidney function, was not significantly different between the groups. The authors report that baseline data demonstrated elevated inflammation and low antioxidant levels.

A significant time effect (P=0.03; effect size [ES]=0.32) and time × compliance interaction effect (P=0.05; ES=0.30) were observed for IL-6, with a decrease in the treatment group and an increase in the placebo group. No significant group, time, or interaction effects were seen for any of the other outcome variables. Noting that these findings partially support earlier research on the anti-inflammatory effects of curcumin and boswellia, the authors write: "Reasons for [only] partial support of previous literature could be due to a dose-response relationship, short study duration, influence of anti-inflammatory medications, small sample size, or lack of interaction between curcumin, Boswellia serrata, and some markers of inflammation." CRP and IL-6 have been shown to be significantly correlated.1 The authors explain that the lack of change in CRP in this study may be due to the high prevalence of nonsteroidal anti-inflammatory drug use by the study subjects, as most patients were taking aspirin to reduce the risk for myocardial infarction, which may have inhibited curcumin's effectiveness against CRP.

According to the authors, the lack of a statistical change in GPx levels may be due to the study duration and sample size: "A supplementation period of 8 weeks may have been of insufficient magnitude to observe changes in GPx, and the sample size used in the present study was small, with larger studies needed to determine if curcumin's antioxidant benefits observed in animal studies carry over to humans."

Only minor adverse side effects were reported during the study.

These results support those of previous studies suggesting that CKD is associated with an ongoing inflammatory state and impaired antioxidant activity. The study treatment was well tolerated and resulted in decreased inflammation as measured by IL-6; however, no changes were observed in any other inflammatory or antioxidant markers.

Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a “super curcumin” through improvement of the bioavailability to bring this promising natural product to the forefront of diabetes therapeutics.

ConclusionRecent research has provided the scientific basis for “traditional” curcumin and confirmed the important role of curcumin in the prevention and treatment of diabetes and its associated disorders. Curcumin could favorably affect most of the leading aspects of diabetes, including insulin resistance, hyperglycemia, hyperlipidemia, and islet apoptosis and necrosis (Figure 2). In addition, curcumin could prevent the deleterious complications of diabetes. Despite the potential tremendous benefits of this multifaceted nature product, results from clinical trials of curcumin are only available in using curcumin to treat diabetic nephropathy, microangiopathy and retinopathy so far. Studies are badly needed to be done in humans to confirm the potential of curcumin in limitation of diabetes and other associated disorders. Further, multiple approaches are also needed to overcome limited solubility and poor bioavailability of curcumin. These include synthesis of curcuminoids and development of novel formulations of curcumin, such as nanoparticles, liposomal encapsulation, emulsions, and sustained released tablets. Enhanced bioavailability and convinced clinical trial results of curcumin are likely to bring this promising natural product to the forefront of therapeutic agents for diabetes by generating a “super curcumin” in the near future.

The degenerative joint disease osteoarthritis (OA) is physically debilitating and significantly impairs quality of life. As the cause of OA remains unknown, current medical treatment is directed towards alleviating pain and restoring movement using nonsteroidal anti-inflammatory drugs (NSAIDs). However, long term use of NSAIDs is associated with significantly increased risk of gastrointestinal, renal, and cardiovascular adverse effects. Turmeric (Curcuma longa) rhizome has been shown to have both anti-inflammatory and antioxidant activity. In clinical trials, boswellia (Indian frankincense; Boswellia serrata) gum resin has shown positive effects in treating both rheumatoid arthritis and OA. This randomized, observational trial tested the efficacy of a turmeric and boswellia (CB) combination in comparison to celecoxib (a standard NSAID) in alleviating the symptoms of knee OA.

The CB combination consisted of 350 mg of turmeric extract standardized to contain 70% curcumin, 17% demethoxycurcumin, 3.5% bisdemethoxycurcumin, and 7.5% turmeric essential oils, and 150 mg boswellia extract consisting of 75% boswellic acids and 10% 3-O-acetyl-11-keto-boswellic acid (AKBA). Although the turmeric constituent curcumin has been shown to have significant anti-inflammatory activity, oral bioavailability is very poor. A formulation providing improved curcumin bioavailability was used in this study. And while the boswellia constituent AKBA also has significant anti-inflammatory activity, the authors point out that most commercial boswellia extracts contain a relatively low concentration of AKBA (~2%). The boswellia extract used in this study was "enhanced" to contain 10% AKBA. The CB combination was provided in 500 mg capsules produced by Arjuna Natural Extracts Ltd.; Aluva, Kerala, India. No other information on the proprietary formula was provided.

In this 12-week study, conducted at Anugraha Medical Centre in Kochi, Kerala, India, 30 patients with OA were randomly assigned to receive either 500 mg of CB twice daily or 100 mg of celecoxib 2 times per day. The study included 8 clinic visits where vital signs, OA symptom scores, and physical exam results were recorded. Included patients were men and women between 18-65 years old diagnosed with moderate OA based upon radiographic evidence. Those with gross OA deformity, severe OA, severe swelling and restricted mobility, rheumatoid or reactive arthritis, other systemic diseases, malnutrition, history of alcohol or drug abuse, and breastfeeding women were excluded.

The OA symptoms scored were joint pain (no pain, mild, moderate, or severe), walking distance (greater than 1,000 m, 500-1,000 m, 100-500 m, or less than 100 m), joint tenderness (no tenderness, improved, same, or worsened), and crepitus or crackling sounds (no crepitus, mild, moderate, or severe). Knee swelling and thigh circumference were quantified using a measuring tape and range of movement was assessed in degrees using a goniometer. Joint warmth (yes, no) and gait (normal or abnormal) were also assessed. To evaluate safety, vital signs, hemogram (laboratory blood parameters), and liver and kidney function were measured at baseline, 6 weeks, and 12 weeks. The authors did not indicate whether they queried patients about possible adverse effects.

In total, 28 patients finished the study, with 1 patient from each group dropping out due to personal reasons or uncontrolled symptoms. At baseline, no significant differences were observed in age, height, weight, body mass index (BMI), temperature, blood pressure, pulse rate, or respiration between the groups. Although pain severity significantly improved from baseline to endpoint (P<0.05) in both groups, no significant differences between groups were observed. However, the number of patients improved was markedly higher in the treatment group; 85.71% of patients were classified in the moderate/severe range at baseline, and at endpoint, only 21.43% of patients were in this category. In the control group, 78.57% of the patients had moderate/severe pain at baseline and 50% still had moderate/severe pain at the endpoint.

Improvement in walking distance was seen in both groups (P<0.05), with 92.86% of those in the treatment group and 85.71% of those in the control group able to walk more than 1000 m at endpoint; however, there were no significant differences between groups. Also, both groups had significantly less joint tenderness at the end of the study (P<0.05). In the treatment group, 85.71% had moderate/severe joint tenderness at baseline, and this decreased to 7.14% of patients at the end of the study. Patients in the control group showed a smaller improvement in joint tenderness, declining from 78.57% at baseline to 21.43% of patients after 12 weeks of treatment. Crepitus improved in both groups from baseline to endpoint (P<0.05); there was also a significant beneficial effect seen in range of movement (P<0.05) in both groups. Swelling, joint warmth, gait, and thigh measurements were not changed in either group. Vital signs, blood parameters, and liver and kidney function remained unchanged. No adverse effects were reported in either group.

The authors conclude that improvements in pain severity, walking distance, and joint tenderness were superior in those taking the CB supplement compared to the NSAID control medication and that CB was comparable to celecoxib in increasing range of movement and decreasing crepitus. They state, "The efficacy and tolerability of [the] CB formulation used in the current study was shown to be superior to those of celecoxib (NSAID) for treating active OA."

The authors hypothesized that the CB formulation would be as effective as celecoxib in reducing OA symptoms, and cause fewer adverse effects. While the effectiveness of the 2 treatments appeared to be comparable, no adverse effects were reported in either group. Studies with a larger sample size are needed to confirm the efficacy of CB and to detect differences in the occurrence rate of adverse effects. --Amy C. Keller, PhD

Depression affects many people throughout the world and can be the cause of disruptive health problems, and can even lead to suicide. Although standard pharmaceutical treatments exist, chronic use of them may result in adverse effects. Botanicals may provide therapeutic options for depression with greater tolerability. Curcumin, a compound found in turmeric (Curcuma longa) root, has been shown to alleviate depression previously; suggested mechanisms include impacts on neurotransmitters and the potentiation of other antidepressant pharmaceuticals. This 6-week, randomized, controlled trial investigated curcumin, the standard antidepressant fluoxetine, and a combination of both treatments in patients suffering from major depressive disorder (MDD).

Patients diagnosed with MDD were recruited at Sir Takhtasinhji General Hospital in Bhavnagar, Gujarat, India. Patients were older than 18 years of age, had access to a caregiver, and rated higher than 7 on the Hamilton Depression Rating Scale (17-item version; HAM-D17). This scale rates symptoms of depression, and total scores of 0-7 are considered normal. Those suffering from other severe mental illness, including those with suicidal tendencies, seizures, thyroid disorders, or allergies to the study treatments, were excluded. Those for whom at least 2 other antidepressants had failed to work, those who had taken antidepressants or an "investigational" drug within 30 days prior to the study, and those who were participating in therapy were excluded. Included female patients were using contraception and were not pregnant at the time of the study's beginning.

Curcumin (50-mg capsules) was procured from Arjuna Natural Extracts; Kochi, Kerala, India. Capsules were standardized to contain 88% curcuminoids and 7% volatile oils, and the daily dose of curcumin was 1000 mg. Fluoxetine (20-mg capsules of Flunil-20®) was obtained from Intas Pharmaceuticals; Ahmedabad, Gujarat, India. The fluoxetine dosage was 20 mg per day. Prior to being randomly assigned, patients were subjected to physical and psychiatric exams, laboratory parameters, and vital sign measurements. Patients were randomly assigned to groups taking either fluoxetine only, curcumin only, or both fluoxetine at 20 mg/day and curcumin at 1000 mg/day, for 6 weeks. Curcumin was administered twice daily, 12 hours apart, in 500-mg doses taken after breakfast and dinner. During the first 2 weeks of the study, paracetamol and benzodiazepines were permitted to treat headaches and insomnia, respectively. At 2, 4, and 6 weeks into the study, parameters were measured.

The primary outcome was the HAM-D17 score, followed by the mean change in the score and the remission rate. Secondary outcomes included patients' rate of response on the Clinical Global Impression-Improvement (CGI-I) assessment scale and scores on the Clinical Global Impression-Severity of Illness (CGI-S) scale. The CGI-I is a 7-point scale where 1 means "very much improved" and 7 means "very much worse"; and the CGI-S is a 7-point scale where 1 means "normal/not at all ill" and 7 means "extremely ill." Safety was assessed by treatment-emergent adverse events (TEAEs), the measurement of vital signs, and physical exams during clinical visits. Laboratory parameters were also measured at the end of the study. Those with a HAM-D17 score of ≤ 7 were considered to be in remission; a 50% decline in HAM-D17 scores as compared with baseline scores constituted a response. According to the CGI-I scale, a score of 1 or 2 indicated a response. Efficacy and tolerability were classified as "excellent, good, fair, or poor." Pill counting was done to assess compliance.

Of the patients recruited, 60 were enrolled and were randomly assigned to the 3 groups (n=20 per group). Overall, there were no "major" deviations or violations of the protocol. Because of either loss to follow-up or withdrawal due to adverse effects (fluoxetine group), 45 patients completed the study, with 16 in the fluoxetine group, 14 in the curcumin group, and 15 in the combination group for the per-protocol analysis (the intention-to-treat [ITT] population was n=17 in the fluoxetine group, n=16 in the curcumin group, and n=18 in the combination group). According to the HAM-D17, a greater response to treatment in the ITT population was observed in the combination group compared to the curcumin group and the fluoxetine group; this was not significantly different (77.8% vs. 62.5% and 64.7%, respectively; P=0.58).

At the end of the study, the mean changes in the HAM-D17 scores in the ITT population were not significantly different between the combination group (-14.8; 95% confidence interval [CI]: -17.6, -12.0) and the fluoxetine group (-14.0; 95% CI: -18.2, -9.8) or the curcumin group (-12.6; 95% CI: -15.8, -9.5; P=0.77). This was also true of the rate of remission (P=0.58), and the results were the same in the per-protocol analysis. The efficacy rating was either "excellent" or "good" for 70.5% of those in the fluoxetine group, 75% of those in the curcumin group, and 83.3% of those in the combination group; there were no significant differences between them (P=0.66).

TEAEs were observed in 2 patients in the fluoxetine group, 2 in the curcumin group, and 5 in the combination group. Adverse effects were classified as "mild" and included gastritis, giddiness, hot flashes, nausea, photosensitivity, and mouth ulcers. No significant differences were seen at the end of the study as compared to baseline in patients' laboratory or physical parameters. Although tolerability was rated as "excellent" for 82.3% of those in the fluoxetine group and 87.5% of those in the curcumin group as compared with 66.6% of those in the combination group, these differences were not significant (P=0.30).

This study showed curcumin to have similar efficacy as fluoxetine. It is suggested that curcumin's bioactivity may be due to effects on neurotransmitters such as serotonin, or the concurrent potentiation of antidepressant pharmaceuticals. This study also shows curcumin to be well tolerated, with no serious adverse effects. It is discussed that curcumin's bioavailability was improved through the addition of curcuminoids and volatile oils, although this additive process is not described in the methods. Discussed shortcomings of this trial include the intentionally small sample size and the absence of a placebo group. Also, patients were not blinded to the treatments. A future, double-blind, placebo-controlled clinical trial will likely confirm curcumin as a good candidate for the treatment of MDD, both alone and in combination with standard treatments.

AbstractHeart failure is one of the leading causes of death throughout the world. During the development and deterioration processes of heart failure, cardiomyocytes undergo maladaptive hypertrophy by altering hypertrophy-related gene expression. The zinc finger protein GATA4 is one of the transcription factors involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as the synaptic nervous and rennin-angiotensin systems, GATA4 forms a large complex with various functional proteins including an intrinsic histone acetyltransferase, p300, and the disruption of this complex results in the inhibitionof hypertrophic responses in cardiomyocytes. While such a transcriptional signal pathway is recognized as a critical event during cardiomyocyte hypertrophy, pharmacological heart failure therapy that targets this pathway has not been established. In order to develop novel heart failure therapy targeting the pathway in cardiomyocytes, we have studied the potential of curcumin, a p300 histone acetyltransferase inhibitor, as an agent for novel heart failure therapy. In this review, we describe a recent study on the cardiac transcriptional signal pathway, especially p300/GATA4 pathway, and a novel heart failure therapy using curcumin.

More than 300 million people worldwide have type 2 diabetes mellitus (T2DM), and its prevalence continues to increase. Persons with prediabetes (having blood glucose levels higher than normal but not high enough to be diagnosed as diabetes) can often prevent the development of the disease by making lifestyle changes, but those changes are often challenging. Effective therapeutic agents, with relatively low cost and low toxicity, are needed to control the progression of the disease. Curcumin, the principal curcuminoid in turmeric (Curcuma longa), has been shown to possess anti-inflammatory and antidiabetic properties. These authors conducted a randomized, double-blind, placebo-controlled trial to determine the effectiveness of a curcuminoid extract in preventing the development of T2DM.

The 12-month trial was conducted at the HRH Princess Maha Chakri Sirindhorn Medical Center of Srinakharinwirot University in Nakornnayok, Thailand. Eligible subjects were instructed to follow the same protocols for diet and exercise for 3 months after enrollment while awaiting randomization. Standard lifestyle recommendations were provided, and all subjects were counseled one-on-one on the importance of a healthy lifestyle.

Persons aged 35 years and older with prediabetes, as defined by the American Diabetes Association (ADA) guidelines, were included. Eligible subjects had at least 1 of these 3 criteria: fasting plasma glucose (FPG) between 100 mg/dL and 124 mg/dL; an oral glucose tolerance test (OGTT) at 2 hours post-glucose load between 140 mg/dL and 199 mg/dL; and a glycated hemoglobin (HbA1c) range from 5.7% to 6.4%.

The 237 subjects (with 3 dropouts after randomization) were randomly assigned to either the curcumin-treated group (n=118) or the placebo-treated group (n=116). Baseline characteristics were similar between the 2 groups.

All subjects were instructed to take 3 capsules twice daily for 9 months. The curcuminoid extract was prepared by extracting dried, powdered turmeric with ethanol and removing the oleoresin. Each curcumin capsule contained 250 mg curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin in a peak ratio of 1:≤0.6:≤0.4, respectively). Compliance rates were determined by the number of capsules the subjects returned at their follow-up visits at 3, 6, and 9 months.

The primary outcome was the number of subjects in the 2 groups diagnosed with T2DM according to ADA guidelines. Secondary outcomes were changes in β-cell functions (homeostasis model assessment [HOMA]-β, C-peptide, and proinsulin/insulin ratio); insulin resistance (IR) by HOMA-IR; obesity; abdominal obesity; and anti-inflammatory cytokine (adiponectin). β-cells store and release insulin, which controls the level of glucose in the blood.

The authors report that at all visits (months 3, 6, and 9), the diabetes-related blood chemistries (FPG, OGTT at 2 h, and HbA1c) used to measure the progression of the disease were all significantly lower in the curcumin-treated group compared with the placebo-treated group (P<0.01). For example, at month 9, FPG in the curcumin-treated group was 86.47 mg/dL (range=73-122 mg/dL) compared with 108.21 mg/dL (range=80-138 mg/dL) in the placebo-treated group. Mean baseline FPG values were 103.65 mg/dL in the curcumin-treated group and 103.24 mg/dL in the placebo-treated group.

In their assessments of β-cell function, the authors discovered that HOMA-β in the curcumin-treated group was increasingly elevated at all follow-up visits and became statistically significant at month 9 (P<0.01). C-peptide levels were significantly lower in the curcumin-treated group compared with the placebo-treated group at 9 months (P<0.05). The proinsulin/insulin ratio showed a nonsignificant, lower trend in the curcumin-treated group.

The mean levels of HOMA-IR were lower in the curcumin-treated group than in the placebo-treated group at all visits. The differences were significant at months 6 (P<0.05) and 9 (P<0.001). Adiponectin levels, unchanged in the placebo-treated group, gradually increased at months 3 and 6 in the curcumin-treated group and became significantly different than the placebo-treated group at month 9 (P<0.05).

None of the subjects in either group showed any change in kidney or liver functions. A few subjects in the curcumin-treated group reported minor adverse side effects such as itching, constipation, or vertigo.

The authors report that none of the subjects in the curcumin-treated group developed T2DM in regard to the primary outcome; however, the following numbers of subjects in the placebo-treated group developed T2DM: 11 (9.5%) at month 6; 18 (15.5%) at month 9; and 19 (16.4%) at month 12.

The authors note that the conversion rate of the placebo group was significantly higher than that published in a "well-known" American study.1 They reasoned that the ethnicity of the subjects in their study may account for the high conversion rate. They compared their results with those of a diabetes study of a large Thai cohort2 that identified a set of strong risk factors that accelerate the development of T2DM among the Thai population: old age, high body mass index, high waist circumference, hypertension, and a family history of diabetes. They found that the same factors influenced their study and that their reported rate of development of T2DM was within the estimation of the earlier study.2 "Therefore, we believe that the high conversion rates found in the present study are a common characteristic of Thai prediabetes," they write.

These authors report that the ethanol-extracted curcuminoids used in this study substantially and significantly prevented T2DM development in subjects with prediabetes. They also found that the curcuminoid extract improved β-cell functions.

"Because of its benefits and safety, we propose that curcumin extract may be used for an intervention therapy for the prediabetes population," they write.

Rheumatoid arthritis is a chronic systemic inflammatory disorder that is distinguished from other forms of arthritis by the joint destruction that is its prominent feature. Typically, 30% of patients do not respond to the classic forms of treatment. Curcumin, the major active constituent of the spice turmeric (Curcuma longa, Zingiberaceae), has been shown to modulate numerous pathways related to inflammation. This randomized, single-blind, pilot study examined the efficacy and safety of a curcumin extract in comparison to, and in combination with, diclofenac sodium (a pharmaceutical non-steroidal anti-inflammatory drug [NSAID]) in patients with mild-to-moderate rheumatoid arthritis (RA).

The study was conducted at Nirmala Medical Centre in Muvattupuzha, Kerala, India, and included 45 patients (38 females and 7 males; mean age=47.88 years) with RA according to the revised 1987 American College of Rheumatology (ACR) criteria (with RA functional class I or II) and Disease Activity Score 28 (DAS28) > 5.1. Patients were excluded if they were taking NSAIDs or other anti-arthritic therapies, had any complicating surgeries or diseases, were pregnant or nursing, or had a history of substance abuse. Patients were divided into 3 groups: curcumin extract (500 mg BCM-95®; Arjuna Natural Extracts; Kochi, Kerala, India; imported and sold in the United States as CuraMed® by EuroPharma; Green Bay, WI), diclofenac sodium (50 mg; no source given), or both in combination; treatments were taken twice a day for 8 weeks. Neither the article nor the manufacturer’s website describes standardization.

Data on demographic characteristics, medical history, and medications were collected at baseline. Body weight, blood pressure, and heart rate were recorded, and hematology, blood chemistry, C-reactive protein (CRP), antistreptolysin-O (ASO), and blood sugar tests were performed. Each patient underwent an X-ray with an anteroposterior (AP) view of chest/hands/wrist/foot and 12-lead electrocardiography as well as a 28-joint assessment for tender joint count, swollen joint count, and duration of morning stiffness.

There was no significant difference in any baseline characteristics between the groups. Thirty-eight patients completed the study and were included for efficacy analyses; all 45 patients were included in safety assessments. No explanation is given as to the reasons 7 patients did not complete the study.

There was a statistically significant change in DAS28 scores compared to baseline of similar proportion for all 3 treatment groups after 8 weeks (all P<0.05). There was no significant difference among the groups. Likewise, each group had a statistically significant difference in the ESR and VAS (all P<0.05) compared to baseline, but not among groups; curcumin extract had the highest percentage change of the 3 groups for VAS (59.9%). There was also a statistically significant change in ACR scores in all 3 treatment groups (all P<0.05), but no difference among them. The authors report that the percentage change in ACR was greatest for curcumin. CRP showed a significant change only in the curcumin group (P<0.05).

Adverse events were reported more frequently in the diclofenac sodium group and included itching and swelling around the eyes, dimness of vision, and worsening of the condition. Adverse events reported in the curcumin group were mild fever and throat infection (which are not necessarily associated with the use of the curcumin).

This pilot study shows that BCM-95 curcumin reduced DAS28 and ACR scores in patients with RA alone or in combination with diclofenac sodium. It also showed that intake levels of 500 mg twice daily for 8 weeks yielded few adverse effects. The mechanism for this action is not known but is purported to be due to the effect of curcumin on multiple signaling pathways involved with pain and inflammation. The authors reported that BCM-95 curcumin was selected for use in this study based on its enhanced absorption, which has been shown in 2 previously published human studies to have up to 7 times increased absorption than generic 95% curcumin turmeric extracts based on area under the curve (AUC) and 10 times the serum peak of generic 95% curcumin extracts.1,2

The authors conclude by asserting that BCM-95 curcumin extract was the superior treatment in this study, based on its efficacy equaling the prescription drug diclofenac sodium on DAS28 and ACR scores, combined with its superior safety and lower adverse effect profile. What can be said is that this proprietary curcumin extract had a similar effectiveness to the prescription drug diclofenac sodium with few adverse side effects. Larger studies will help to shed light on these findings.

Comparison of the effects of curcuminoid from Curcuma domestica Val. rhizome extract and diclofenac sodium on the liver function of patients with osteoarthritisNyoman Kertia1*, Ahmad Husain Asdie2, Wasilah Rochmah3 and Marsetyawan4

Osteoarthritis is the most frequent joint disease worldwide. Patients with osteoarthritis mostly use non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac sodium for reducing pain. Diclofenac sodium frequently disturbs the liver function. Curcuminoid has an anti-inflammatory activity and some references state that curcuminoid protects the liver function. The purpose of this study was to compare the effects of curcuminoid from Curcuma domestica Val. rhizome extract and diclofenac sodium on the liver function of patients with osteoarthritis. A total of 80 patients with knee osteoarthritis were enrolled. Subjects were divided randomly into two groups; a group received 30 mg of curcuminoid from C. domestica Val. 3 times daily (curcuminoid group) and the other received 25 mg of diclofenac sodium 3 times daily (diclofenac group). Assessment of results includes serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) performed before and after 4 weeks of treatment. In the curcuminoid group, there was no significant decrease of AST serum level (p < 0.15) and ALT serum level (p < 0.41), whereas in the diclofenac group, there was no significant increase of AST serum level (p=0.05) and significant increase of ALT serum level (p<0.01). The increase of serum AST and ALT level in the diclofenac group were significantly different as compared to the decrease of the levels in the curcuminoid group. This means that diclofenac sodium disturbs liver function, while curcuminoid from C. domestica Val. rhizome extract improves the liver function of patients with osteoarthritis.

According to the authors, the incidence of non-Hodgkin's lymphoma (NHL) is increasing, making it the fifth most common cancer in Egypt. Elevated levels of apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) in cancers are indicators of poor prognosis and chemotherapeutic resistance, and the removal of APE1 sensitizes cancer cell lines to chemotherapeutic agents.1 The efficacy of chemotherapy is increased with the multitargeted regulation of multiple signaling pathways, including nuclear factor-kappa B (NF-ĸB), cyclooxygenase-2, apoptosis, and others. These authors hypothesized that curcumin, a polyphenolic antioxidant derived from turmeric (Curcuma longa), and epigallocatechin-3-gallate (EGCG) from green tea (Camellia sinensis) would increase the efficacy of chemotherapy in patients with follicular lymphoma (FL), a type of NHL. They evaluated the antitumor effect of curcumin and EGCG in combination with chemotherapy on peripheral blood mononuclear cells in patients with lymphoma.

Curcumin and EGCG were selected because they are pharmacologically safe agents that have been shown to down-regulate NF-ĸB and NF-ĸB-regulated gene products involved in tumor angiogenesis and metastasis.

The authors recruited 40 subjects: 10 healthy subjects (control group) and 30 subjects diagnosed with FL (FL group). The 18 men and 12 women that made up the FL group were diagnosed with FL at different stages, with histological subtypes.

Blood samples were drawn from all subjects at baseline, and at 3, 6, 9, and 12 months. Physical activity and the extent of disease were assessed at baseline.

During the study period, the subjects in the FL group were treated for 9 months with either the chemotherapy regimen CHOP, CHOP with curcumin, or CHOP with curcumin and EGCG (CHOP includes cyclophosphamide, hydroxydaunorubicin [also called doxorubicin or Adriamycin], oncovin [vincristine], and prednisone or prednisolone). Subjects were followed for 3 months subsequent to the 9-month treatment.

CHOP resistance was defined as occurring in subjects whose disease progressed during first-line CHOP chemotherapy or who relapsed within 6 months after treatment. Drug resistance is a major cause of relapse and the incurability of cancer. The effect of the herbal therapy to overcome the drug resistance of FL subjects to chemotherapy was estimated by determining glutathione s-transferase (GST) activities. GST helps defend against free radicals, peroxides, xenobiotics, and carcinogens.

Attainment of complete remission was the most important predictor of overall survival; low serum lactate dehydrogenase (LDH), limited stage disease, and a high serum albumin were also independently associated with prolonged survival.

The authors report that adding curcumin and EGCG to the CHOP treatment significantly lowered cytoplasmic APE1, and the levels of the transcription factor were lower than those predicted from the effects of the CHOP agents alone. Eighteen of the subjects had a complete remission, and 12 patients had partial remission within the 9-month treatment period and the 12-month follow-up period. They remained disease-free for a mean of 8.6 years (range=7.9-9.2 years) after the combination therapy. According to the authors, this report provides the first data demonstrating a role of APE1 in lymphoma patients' survival and function after CHOP treatment.

In those subjects treated with a combination of CHOP, curcumin, and EGCG, the serum levels of the angiogenic vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were significantly higher than those of the control subjects before treatment. Significantly reduced serum levels of both factors were reported in all subjects receiving the combination of CHOP, curcumin, and EGCG as a first response of the treatment. No P values were given.

Further results indicate that adding curcumin to CHOP improved the International Prognostic Indices (β2 microglobulin and LDH activity) and caused a significant decrease in both groups of combination therapy after 6 and 9 months of treatment, while with green tea, the effect was greater than that of curcumin alone. The chemotherapy-treated group did not show any significant difference in both factors. The decrease in these parameters was a good prediction for complete remission rate and a good prognostic effect of both curcumin and green tea, say the authors.

GST activity showed a marked increase in the CHOP-only group after 9 months of treatment and at the 3 month follow-up, while in both combination therapy groups, GST activity showed a significant decrease. "This gives us an idea about the ability of both adjuvant therapies (curcumin and EGCG) to overcome the resistance of NHL patients to chemotherapy," write the authors.

Evaluation of hepatic and renal function during treatment indicated the absence of any adverse side effects of the studied adjuvant therapy (curcumin and green tea) in combination with chemotherapy.

Treatment of patients' cells with the combination of CHOP, curcumin, and EGCG for 9 months induced significant cell death versus the control, CHOP, or CHOP and curcumin-treated cells. The number of viable cells reduced significantly (P<0.05).

The authors conclude that in the subjects with FL, the combination of curcumin and EGCG resulted in a synergistic antitumor activity and, with CHOP agents, down-regulated the expression of all NF-ĸB-regulated gene products, leading to the suppression of angiogenesis, metastasis, and entering in complete remission as indicated by β2 microglobulin and LDH levels. The addition of curcumin and EGCG to CHOP achieved long-lasting remissions in 18 of 30 (60%) subjects with FL. "These data suggest that the combination of curcumin, EGCG, and CHOP is [a] highly effective palliative regimen for patients with FL with good performance status," write the authors.

Periodontal disease and gingivitis affect a majority of the population and are thought to be caused by bacterial plaque. Toothpastes and mouthwashes are the best adjunct to mechanical cleaning for plaque build-up, and the dentistry gold standard compound for plaque is chlorhexidine gluconate (CHX). It does have adverse side effects, such as discoloration of the teeth, bitter taste, and mucosal erosion, and alternative remedies are desirable. Turmeric (Curcuma longa) has a number of properties such as anti-inflammatory, antioxidant, and antimicrobial activity that could make it a useful dental preventative treatment. This randomized, double-blind, comparative study examined the efficacy of CHX and turmeric mouthwashes in healthy, young adults.

The study was conducted in the Department of Periodontology, Bharati Vidyapeeth Dental College and Hospital, Pune, India. Subjects (aged 25-35 years) having fair to poor Loe and Silness gingival index scores and Turesky-Gilmore-Glickman modified Quigley-Hein plaque index scores >1 were included in the study. Exclusion criteria included those with systemic diseases, those wearing oral appliances or whose habit it was to breathe out of their mouth, pregnant or lactating females, and smokers. The study included 100 subjects who were randomly given either CHX mouthwash (ICPA Health Products Limited; Maharashtra, India) or turmeric mouthwash (10 mg curcumin extract dissolved in 100 ml of water with a peppermint flavoring agent added; no information on the source of the curcumin extract given). Subjects (n=50 in each group) were asked to gargle with 10 ml of mouthwash in a 1:1 dilution with water twice a day after brushing. Subjects recorded their use of the mouthwash as a check of compliance, and oral hygiene instructions were given at the beginning and again to those whose compliance faltered during the course of the study. Both the gingival index and plaque index scores were recorded on days 0, 14, and 21. Plaque was collected from the tooth surface of 5 subjects in each group and analyzed for bacteria on days 0 and 21.

Both groups had a significant decrease in the plaque index from baseline after 14 days, and an even greater decrease after 21 days (CHX 1.59 ± 0.33 and 2.48 ± 0.48 below baseline, respectively, P < 0.01 for both; and turmeric 1.27 ± 1.86 and 2.05 ± 0.48 below baseline, respectively, P < 0.01 for both). There was a statistically significant difference in the plaque index between the 2 groups in favor of the CHX mouthwash (74.36% decrease for CHX and 61.76% decrease for turmeric, from day 0 to day 21, P < 0.05). Both groups also had a significant decrease in the gingival index from baseline after 14 days, and an even greater decrease after 21 days (CHX 0.90 ± 0.15 and 1.04 ± 0.67 below baseline, respectively, P < 0.01 for both; and turmeric 0.90 ± 0.12 and 1.1 ± 0.11 below baseline, respectively, P < 0.01 for both). A reduction in the gingival index shows a reduction in inflammation. There was no statistically significant difference in the gingival index between the 2 groups. There was a significant reduction in the total bacterial count of both groups after 21 days, down 126.87 ± 51.6 for CHX and down 178.68 ± 28.92 for turmeric (volume units not given; P < 0.05 for both), but there was no difference between the groups.

Both mouthwashes showed efficacy and reduction of inflammation and plaque count, with the CHX mouthwash scoring better on the plaque index. The authors suggest that a possible mechanism of action of the turmeric mouthwash could be "its inhibitory action on prostaglandin synthesis and a strong stabilizing action on the lysosomal membranes." They conclude that turmeric mouthwash could be a good adjunct to mechanical plaque control. Further study is suggested to determine optimal concentration for antiplaque activity and individual periodontopathogen sensitivity.

The medicinal properties of turmeric (Curcuma longa), the source of curcumin, have been known for thousands of years, but advancements in modern science have provided a scientific basis for using curcumin therapy against numerous human diseases. In this article, the authors discuss the discovery and key biological activities of curcumin, particularly its activities at the molecular and cellular levels, as well as in animals and humans.

The discovery of curcumin dates back 2 centuries ago when Vogel and Pelletier1 isolated "yellow colouring matter" from the rhizomes of turmeric and named it curcumin (the word curcumin stems from the Persian word "kurkum" [curcuma], which means saffron). Later, the substance was found to be a mixture of resin and turmeric oil. For several decades, chemists reported possible structures of curcumin; however, in 1910, the chemical structure of curcumin was identified as diferuloylmethane or 1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E).

Although turmeric has been used as a dietary spice and a cure for human ailments for thousands of years in Asian countries, the biological characteristics of curcumin were not identified scientifically until the mid-20th century. In a paper2 published in Nature in 1949, the authors reported that curcumin was active against strains of Staphylococcus aureus, Salmonella paratyphi, Trichophyton gypseum, and Mycobacterium tuberculosis. In the 1970s, the cholesterol-lowering, antidiabetic, anti-inflammatory, and antioxidant activities of curcumin were reported, and in the 1980s, its anticancer activity in both in vitro and in vivo models was reported.3 By 1995, anti-inflammatory activity and the mechanisms involved were elucidated by the authors.4

Although curcumin is effective against many human ailments, it has poor bioavailability, apparently due to its poor absorption, rapid metabolism, and rapid systemic elimination. Efforts have been made to improve its bioavailability by improving these factors. In spite of these limitations in bioavailability, as little as 150 mg curcumin administered twice a day orally in humans (n=23) was sufficient to lower serum levels of inflammatory biomarkers such as endothelin-1, interleukin-6, tumor necrosis factor-α and malondialdehyde levels.5

Curcumin is now regarded as a "new drug" with great potential and is being used as a supplement and marketed in several forms, including capsules, tablets, ointments, energy drinks, soaps, and cosmetics.

Curcumin has been shown to modulate various signaling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA, and metal ions. Curcumin may cause up- or downregulation, depending on the target and cellular context. These targets fall into 2 categories: those to which curcumin binds directly and those whose activity is modulated indirectly by curcumin; both of these areas are extensively covered in review articles. Among the most important targets of curcumin are the pro-inflammatory transcription factors, which regulate the expression of genes that contribute to tumorigenesis, cell survival, cell proliferation, invasion, and angiogenesis. Another important target is the protein kinases.

Because it modulates multiple signaling molecules, curcumin has been reported to possess pleiotropic activities. In vitro, it has been shown to possess anti-inflammatory, antioxidant, pro-apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic, and antimalarial properties.

Curcumin has also been shown to have activity as an antioxidant and free radical scavenger in several in vitro studies. This activity is due to either the hydroxyl group or the methylene group of the α-diketone (heptadiene-dione) moiety. It is also cytotoxic to cancer cells, via the mechanism of apoptosis, and has wide antimicrobial activity.

In animal studies, curcumin has been found to be active against diabetes, obesity, neurological and psychiatric disorders (such as depression, Alzheimer's disease, and Parkinson's disease), and cancer (particularly colon cancer) and cancer-related symptoms such as fatigue, neuropathic pain, and cognitive deficit. It has also shown potential against chronic illnesses affecting the eyes, lungs, liver, kidneys, and gastrointestinal and cardiovascular systems.

About 50 clinical trials have been completed on curcumin's potential in humans. Most have suggested that curcumin is safe and effective to treat a number of diseases, with the most promising effects observed with cancer, inflammatory conditions, skin, eye and neurological disorders, diabetic nephropathy, and pain. Other trials have investigated the role of curcumin in improving body weight and reducing lipid levels in patients with acute coronary syndrome. At the time of this article's preparation, curcumin was undergoing investigation in more than 30 clinical trials, say the authors, adding, "We expect that the completion of these clinical trials will provide further credence to the already established positive effects of curcumin."

Curcumin has not yet been approved to treat any human diseases, say the authors, who suggest that more extensive and well-controlled human studies are needed to demonstrate its safety and efficacy. "Future research should be focused on bringing this fascinating molecule to the forefront of therapeutic agents for the treatment of human diseases," they write.

A compound in the spice turmeric may be an effective way to prevent protein clumping—the first step in Parkinson’s disease

Researchers led by Basir Ahmad, a postdoctoral researcher at Michigan State University, demonstrated earlier this year that slow-wriggling alpha-synuclein proteins are the cause of the clumping, or aggregation.

“Our research shows that curcumin can rescue proteins from aggregation, the first steps of many debilitating diseases,” says Lisa Lapidus, associate professor of physics and astronomy at MSU who co-authored the paper with Ahmad.

Lapidus’ lab uses lasers to study protein folding. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don’t know how they are built—a process known as folding.

The new research sheds light on the process by correlating the speed at which protein folds with its tendency to clump or bind with other proteins.

When curcumin attaches to alpha-synuclein it not only stops clumping, but it also raises the protein’s folding or reconfiguration rate. By bumping up the speed, curcumin moves the protein out of a dangerous speed zone allowing it to avoid clumping with other proteins.

Finding a compound that can fix a protein when it first begins to misfold can lead scientists to identify drugs that can treat certain diseases. But doctors won’t be prescribing curcumin pills any time soon, Lapidus says.

“Curcumin’s usefulness as an actual drug may be pretty limited since it doesn’t go into the brain easily where this misfolding is taking place,” she says.

“But this kind of study showcases the technique of measuring reconfiguration and opens the door for developing drug treatments.”

BackgroundIncrease of blood pressure is accompanied by functional and morphological changes in the vascular wall. The presented study explored the effects of curcuma and black pepper compounds on increased blood pressure and remodeling of aorta in the rat model of experimental NO-deficient hypertension.

ResultsThe increase of blood pressure caused by L-NAME was partially prevented by piperine and curcumin, but the effect of their combination was less significant. Animals with hypertension had increased wall thickness and cross-sectional area of the aorta, accompanied by relative increase of PTAH positive myofibrils and decrease of elastin, collagen and actin content. Piperine was able to decrease the content of myofibrils and slightly increase actin, while curcumin also prevented elastin decrease. The combination of spices had similar effects on aortic morphology as curcumin itself.

ConclusionsAdministration of piperine or curcumin, less their combination, is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. The spices modify the remodeling of the wall of the aorta induced by hypertension. Our results show that independent administration of curcumin is more effective in preventing negative changes in blood vessel morphology accompanying hypertensive disease.

AbstractInflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

Below is an article on Curcumin care of Dr. Mercola and also Dr. Mercola's comments and how to best take curcumin. Also I have uploaded a few scientific studies on Curcumin from our sister site Evidence Based Natural Health.

The Spice that Actually Doubles as a Powerful Anti-Inflammatory

In cultures that are thousands of years old, there tend to be deep traditions of cooking daily meals with medicinal roots and herbs. Turmeric is one such medicinal root that has made its way into many Indian recipes. Research shows that turmeric has powerful anti-inflammatory, anti-tumor and antioxidant properties. Inflammation, if left untreated, can become a chronic health issue. And unlike aspirin or ibuprofen, turmeric's curcumin reduces inflammation naturally, without damaging the liver or kidneys.

Healthier Talk reports:

"It has been found especially helpful in treating conditions like arthritis, sports injuries, irritable bowel syndrome, Crohn's disease, tendonitis and various autoimmune diseases. Some research even suggests that curcumin may also help those suffering asthma, inflammatory bowel disease and, yes, even cancer."

Dr. Mercola's Comments

Ayurveda, an ancient holistic system of medicine and natural healing from India, is based on preventive medicine, and this is why you'll often see a variety of medicinal herbs and spices built right into their daily meals.

This includes not only the wonderfully fragrant and flavorful ginger, chili and cardamom, but also turmeric, which is widely used as an ingredient in the region's well-known curry dishes.

Eastern cultural traditions, including traditional Chinese medicine and Ayurveda, have valued turmeric for its medicinal properties and warm, peppery flavor for more than 5,000 years. Curcumin -- the pigment that gives turmeric its yellow-orange color -- is the active ingredient behind many of the emerging health benefits …

A Powerful Natural Anti-Inflammatory Curcumin is most known for its potent anti-inflammatory properties. The compound has been shown to influence more than 700 genes, and it can inhibit both the activity and the synthesis of cyclooxygenase-2 (COX2) and 5-lipooxygenase (5-LOX), as well as other enzymes that have been implicated in inflammation.

Inflammation is a normal and beneficial process that occurs when your body's white blood cells and chemicals protect you from foreign invaders like bacteria and viruses.

You need some level of inflammation in your body to stay healthy, however it's also possible, and increasingly common, for the inflammatory response to get out of hand.

If your immune system mistakenly triggers an inflammatory response when no threat is present, it can lead to excess inflammation in your body, a condition linked to asthma, allergies, autoimmune disease, heart disease, cancer and other diseases, depending on which organs the inflammation is impacting.

Inflammatory processes also cause irritation to tissues characterized by pain, redness, swelling and heat, such as is often experienced by osteoarthritis patients.

Curcumin's anti-inflammatory effects help to reduce these symptoms; one recent study found that osteoarthritis patients who added 200 mg of curcumin a day to their treatment plan had reduced pain and increased mobility, whereas the control group, which received no curcumin, had no significant improvements.

Other research also found that a turmeric extract composed of curcuminoids (plant-based nutrients that contain powerful antioxidant properties) blocked inflammatory pathways, effectively preventing the launch of a protein that triggers swelling and pain.

Many patients turn to non-steroidal anti-inflammatories (NSAIDs) and analgesics, like Tylenol, for pain relief, but the regular, chronic use of these types of medications is associated with significant, and very serious, side effects such as cardiovascular problems, gastrointestinal harm and kidney and/or liver damage. Curcumin may be able to provide safe, natural pain relief, provided it is absorbed (more on this later).

People in India Refer to Turmeric as "Holy Powder" India has long revered turmeric as "holy powder," and has used it for centuries to treat wounds, infections, and other health problems. Modern research is now confirming many of its folklore claims, finding an astonishing array of antioxidant, anti-cancer, antibiotic, antiviral and other properties.

A general immune system booster due to its high antioxidant capacity, turmeric is 5 to 8 times stronger than vitamins C and E, and even strong enough to scavenge the hydroxyl radical, which is considered by some to be the most reactive of all oxidants.

In India where turmeric is widely used, the prevalence of four common U.S. cancers -- colon, breast, prostate and lung -- is 10 times lower. In fact, prostate cancer, which is the most frequently diagnosed cancer in U.S. men, is rare in India and this is attributed, in part, to the curcumin in turmeric.

Dr. William LaValley from Austin, Texas is one of the top natural medicine cancer physicians I know and he recently shared this important information with me. Interestingly, curcumin actually has the most evidence based literature backing up its anti-cancer claims of any other nutrient!

For instance, studies looking into this potential cancer-fighting link have found curcumin may:

Inhibit the transformation of cells from normal to tumor, as well as inhibit the proliferation of tumor cells already existing

Inhibit the synthesis of a protein thought to be instrumental in tumor formation

Prevent the development of additional blood supply necessary for cancer cell growth (known as anti-angiogenesis)

Curcumin affects over 100 different pathways once it gets into a cell. Interestingly, this also applies to the metabolite of curcumin and its derivatives, which also have anti-cancer properties. According to researchers from the University of Texas M.D. Anderson Cancer Center, curcumin blocks a key biological pathway needed for development of melanoma and other cancers.

The spice actually stops laboratory strains of melanoma from proliferating and pushes the cancer cells to commit suicide by shutting down nuclear factor-kappa B (NF-kB), a powerful protein known to induce abnormal inflammatory response that leads to an assortment of disorders such as arthritis and cancer.

Curcumin One of the BEST Supplements to Treat Cancer Interestingly just about every alternative medicine expert I know recommends curcumin for just about every type of cancer as it seems nearly universally beneficial. It is the only supplement that I know of that has this benefit. It is very clear that it will be one of the most widely used anti-cancer nutrient approaches in the future.

Chemopreventive potential of curcumin in prostate cancerThese results are consistent with this compound’s ability to up-induce pro-apoptotic proteins and to down-regulate the anti-apoptotic counterparts. Alone or in combination with TRAIL-mediated immunotherapy or radiotherapy, curcumin is also reported to be a good inducer of prostate cancer cell death by apoptosis. Curcumin appears thus as a non-toxic alternative for prostate cancer prevention, treatment or co-treatment.

To get the full benefits that curcumin has to offer, you will want to look for a turmeric extract with at least 95 percent curcuminoids that contains only 100 percent certified organic ingredients.

The formula should be free of fillers, additives and excipients (a substance added to the supplement as a processing or stability aid), and the manufacturer should use safe production practices at all stages: planting, cultivation, selective harvesting, and then producing and packaging the final product.

To fully take advantage of curcumin's therapeutic properties, you'll also need to make sure it is well absorbed.

Tips for Increasing Your Absorption of Curcumin Curcumin is widely available in supplement form, but relatively high doses are required to achieve its anti-cancer effects, and curcumin is generally not absorbed that well. Typical anti-cancer doses are up to three grams of bioavailable curcumin extract, three to four times daily, and this is difficult to achieve using standard curcumin powders.

One alternative is to make a microemulsion by combining a tablespoon of curcumin powder with 1-2 egg yolks and a teaspoon or two of melted coconut oil. Then use a hand blender on high speed to emulsify the powder.

Another strategy you can use to increase absorption is to put one tablespoon of the curcumin powder into a quart of boiling water. It must be boiling when you add the powder, as it will not work as well if you put it in room temperature water and heat the water and curcumin together.

After boiling it for ten minutes you will have created a 12% solution and you can drink this once it has cooled down. The curcumin will gradually fall out of the solution over time and in about six hours it will be a 6% solution, so it is best to drink the water within four hours. It does have a woody taste, but this is done more for therapeutic benefits than flavor.

One caution: curcumin is a very potent yellow pigment and can permanently discolor surfaces if you aren't careful. To avoid "yellow kitchen syndrome" I recommend you perform any mixing under the hood of your stove with the blower on to make sure no powder gets into your kitchen.

You can also use turmeric liberally in your cooking; it has an earthy, peppery flavor. Choose a pure turmeric powder, rather than a curry powder, as at least one study has found that curry powders tend to contain very little curcumin.

Osteoarthritis (OA), a degenerative joint disorder, is a common cause of disability for both men and women. Nonsteroidal antiinflammatory drugs (NSAIDs) are the most common form of treatment for relieving pain associated with OA, but they can cause serious adverse side effects that impact gastrointestinal, renal, and cardiac health. Curcumin present in turmeric (Curcuma longa, syn. C. domestica, Zingiberaceae) extracts has been reported to have anti-inflammatory and antioxidant properties. Researchers from Mahidol University in Bangkok, Thailand conducted a study to determine the efficacy and safety of a turmeric extract in reducing pain and improving function in patients with knee OA.

Conducted at Siriraj Hospital in Bangkok, from April 2005 to May 2006, the study included adult subjects who had primary knee OA according to the American Rheumatism Association criteria. To be included in the study, patients had to have knee pain and radiographic osteophytes, as well as at least 1 of the following characteristics: being older than 50 years of age, suffering from morning joint stiffness lasting less than 30 minutes, and/or experiencing crepitus (crackling in joints) on motion. Patients reporting a pain score of ≥ 5 of 10 in a numerical rating scale were recruited.

The patients were asked to discontinue their medications for knee OA 1 week before randomization. All patients were randomly allocated to receive either ibuprofen (400 mg twice daily) or turmeric extract (500 mg curcuminoids 4 times daily) for 6 weeks.

According to the authors, the turmeric extracts were produced by the Thai Government Pharmaceutical Organization under the Good Manufacturing Practices standard. Dried turmeric rhizomes were ground into powder. The turmeric powder was extracted with ethanol and then evaporated at low pressure to obtain ethanolic extracts containing oil and curcuminoids. The oil was then removed. Each capsule of extract contained 250 mg curcuminoids.

The patients were assessed every 2 weeks. The main outcomes were pain on level walking and pain on stair climbing, measured by a numerical rating scale, as well as knee functions assessed by the time spent on a 100-meter walk and going up and down 10 steps.

All patients had blood tests assessing complete blood count, liver function, and renal function at week 0 and week 6. At week 6, the patients’ satisfaction with treatment was evaluated by a 5-category scale (high, moderate, little, same, or dissatisfaction).

Of 190 patients screened, 107 were selected for the study; 52 were randomly assigned to the curcuminoid group and 55 to the ibuprofen group. Of those, 45 patients in the curcuminoid group and 46 patients in the ibuprofen group completed the study. Most of the patients were overweight (average body mass index greater than 25) elderly women. The duration of symptoms before entering the trial was approximately 20 months. Half of the patients had bilateral knee OA. At baseline, the mean pain scores on level walking and on the stairs, as well as the time spent on the 100-meter walk and on the flight of stairs, were similar between the 2 groups.

The authors report that the mean scores of all outcomes in both groups at week 6 were significantly improved when compared with the baseline values. For example, from week 0 to week 6, the scores for pain on level walking dropped from 5.3 ± 2.3 to 2.7 ± 2.5 for the curcumin group and from 5.0 ± 1.9 to 3.1 ± 2.3 in the ibuprofen group. There was no significant difference in those parameters between the 2 groups, except that pain on stair climbing was less for those taking curcuminoids (P = 0.016). Also, the curcuminoid group seemed to spend less time on the 100-meter walk and going up and down a flight of stairs. No significant differences were found for adverse events between the 2 groups, with dyspepsia (stomach upset; curcuminoids 20.8%, ibuprofen 26.9%) most common. Interestingly, many patients in the curcuminoid extract group who experienced bloating symptoms and passing gas described these symptoms as beneficial gastrointestinal effects, whereas those in the ibuprofen group reported gastrointestinal irritation symptoms.

Regarding satisfaction, most patients rated themselves as having moderate to high satisfaction (91.1% in the curcuminoid group, 80.4% in the ibuprofen group). The patients’ satisfaction with treatment was not statistically significantly different (P = 0.15) between the groups. The patients in the ibuprofen group had better compliance to the treatment regimen than those in the curcuminoid extract group (90.1% versus 82.8%, P = 0.001). This finding was attributed by the researchers to the fact that ibuprofen was given twice a day, whereas curcuminoid extract had to be taken 4 times a day.

These results suggest that curcuminoid extracts of turmeric might be as effective as ibuprofen in alleviating knee pain and improving knee functions, with a trend toward a greater effect in patients receiving curcumin extracts. However, the wide range of 95% confidence interval (CI) indicated that the study had an inadequate sample size; the proper sample size should be 70 patients per groupThe authors recommend more studies with an adequate sample, a higher dose of ibuprofen in the comparison group, and a double-blind technique to demonstrate the efficacy of turmeric extracts in alleviating knee pain and improving knee function.